During the past year, research in the Molecular Immunology Section has been focused on the mechanisms of recognition by human CD8+ T cell antigen-specific receptors (TCRs). Analysis of TCR recognition has been examined using T cell functional assays plus kinetic and thermodynamic binding assays. A particular emphasis of these studies has been on the mechanism of how TCRs recognize the complex of MHC-bound haptenated peptides presented by HLA-A2. The overall conclusion is that there are conserved amino acids on the alpha one (K66) and alpha two (Q155) helices of the HLA-A2 molecule that are key anchor residues that are recognized by most HLA-A2-restricted TCRs, including those that recognize haptenated peptides. For most HLA-A2/peptide complexes whose structures have been solved, the side chains of these key amino acids also contact the bound peptide. These findings demonstrate that the molcular mechanism underlying MHC restriction is that the TCR/MHC interaction cannot be physically separated from the peptide/MHC interaction because key elements of the MHC molecule not only are directly contacted by the TCR but these same MHC elements also contribute to the conformation of the bound peptide. Analysis of TCRs that are specific for structurally diverse haptenated peptides reveals that many TCRs are capable of recognition of quite diverse haptens, and provide a system for analyzing the structural basis of plasticity of TCR recognition. Future studies in this area will focus on the detailed functional analysis of these highly cross-reactive TCRs, the cloning and sequencing of their TCR alpha and beta chain genes, expression of soluble forms of these TCRs for kinetic and thermodynamic binding assays, and crystallographic studies of the TCR/haptenated-peptide/HLA-A2 complexes by our collaborator at the Univ. of Notre Dame. These studies will hopefully provide a biochemical and structural solution to the question of just how much plasticity is associated with TCR cross-reactivity.